There are now over 40 different human amyloid diseases, each linked to the buildup of a specific precursor protein or peptide. These diseases involve the conversion of a protein from its soluble native state into insoluble amyloid fibrils, or, in the case of peptides, the conversion from a soluble, loosely structured form to fibrils. Given that many different sequences can form amyloid fibrils of similar architecture, there may be some common structural features of the prefibrillar amyloidogenic intermediates. X-ray fiber diffraction indicates that the insoluble, mature amyloid fibrils are composed of cross β-sheet structure. Therefore, it is widely held that the formation of amyloid fibrils involves a transition to β-sheet structure in the amyloidogenic intermediate. However, the mechanism of self-assembly at the atomic level remains elusive. Another feature of these diseases is that soluble oligomeric intermediates, not the insoluble well-ordered fibrils, are preferentially responsible for cellular toxicity. Similarly, the soluble oligomeric forms of the prion protein are the most infectious per unit protein. As such, fibrils may be protective, at least up to a point, as their breakdown to smaller aggregates yields greater toxicity and infectivity.